Synthesized β-adrenergic blockers derivatives of guaiacol

ABSTRACT

Compounds of formula I ##STR1## in which OR 1  is --OR 3  NR 4 , in which R3 is a secondary alcohol group with 1.0 to 6 carbon atoms; a cyclic oxygen containing group with two carbon atoms; a pyridylmethyl or a piperidyl-ethyl group, R 2  is alkyl, an ester group, an aldehyde group, a carboxylic acid group or a ketone group with 3 to 6 carbon --O--CONHR 9  atoms, the group O--R 7  NCOR 8  or the group --O--CONHR 9  in which R 4  is an alkyl group with 1 to 8 carbon atoms, R 7  is an alkylene group with 1 to 6 carbon atoms, each of R 8  and R9 is an alkyl group with 1 to 12 carbon atoms and their pharmaceutically acceptable acid addition salts, are selective β-blockers, antagonists of platelet aggregation, and β-receptor binding. The processes of preparation, compositions, method of treatment are also described.

This application is a Continuation-In-Part of U.S. Ser. No. 08/157,473filed Nov. 26, 1993, abandoned.

FIELD OF THE INVENTION

This application relates to β-adrenergic blockers containing theguaiacol ring.

BACKGROUND OF THE INVENTION

Chinese crude drugs or spices eg. Zingiber officinale, Eugeniacaryophyllata, Allium sativum, have been used in medicine and inflavoring foods. Crude ginger is used as an antiemetic and expectorant,an antitussive and accelerator of the digestive organs. Semidried oldcrude ginger is also used for stomachache, chest pain, low back pain,cough, common cold and as a cure for a form of edema being called"stagnate of water". Zingerone is the major component which accounts forthe spicy character of ginger; gingerol and shogaol are other pungentcomponents in ginger. Gingerol has cardio-tonic action, suppresses thecontraction of isolated portal veins in mice, and modulates theeicosanoid-induced contraction of mouse and rat blood vessels. Shogaolexhibits pressor response. Both gingerol and shogaol are mutagenic,whereas zinger and zingerone have been found to exhibit antimutagenicactivity. Shogaol has inhibitory activity on the carrageenin-induced pawedema and platelet aggregation.

It is known that drug-induced physiological responses are mediatedthrough the binding of drugs to their specific receptors in varioustissues and β-receptor blockade has been clinically used incardio-vascular diseases. The pharmacological effects of β-blockers areevaluated based on (1) cardioselectivity, (2) α-adrenergic blockingaction, (3) intrinsic sympathomimetic activity, (4) localanesthetic-activity, and (5) pharmacokinetic parameters related to themetabolism and distribution. Atenolol, Metoprolol, Acebutolol . . . etc.are clinically used as β-blockers and possess cardioselectivity. Somenon-selective β-blockers are suitable for treating bronchial spasm andinsulin-dependent diabetes. The selectivity of β-blockers is determinedby comparing the dosage of each agent needed to produce inhibitoryeffects on β₁ and β₂ receptors in tissues. In addition to in vivo tests,cardiac tissue, adipose tissue, the smooth muscle of trachea, and uterusfrom animals or human lymphocyte are also used to examine theselectivity of β-blockers. It was reported first by Weksler, B. B.(1977), then by Greer, I. A. (1985) that β-blockers affect the plateletfunction.

Further, Srivastava, K. C. reported that lipid soluble β-blockers withmembrane stabilizing activity inhibited the platelet coagulation andthromboxane synthesis. About the action mechanism of β-blockers on theplatelet function, it has been suggested that β-blockers inhibit theactivity of platelet phospholipase A₂ (Greer, I. A. et al, Thromb.Haemost., vol. 54, 480-84) or interfere with intracellular Ca⁺²mobilization (Weksler, B. B. et al, Blood, vol. 49, 185-96). β-blockers,such as Propanolol also inhibit platelet release and the adherence ofplatelets on collagen, but propanolol does not inhibit the shape changeof platelets. The structure-activity relationship between manyβ-blockers and phenoxypropanolamine has been shown by Kierstead, R. W.et al (J. Med. Chem. vol. 26, 1561-69, 1983). They have also shown thatreplacement of the hydrogen atoms with isopropyl group inphenylethylamine produce better affinity with β-blockers.

SUMMARY OF THE INVENTION

An object of the present invention is to provide new guaiacoxypropanolamine derivatives of formula of, I, their relatedpharmaceutically acceptable salts and compositions comprising the samewhich are selective β-blockers, antagonists of platelet aggregation, andβ-receptor binding ##STR2## in which R₁ is alkyl with 1 to 6 carbonatoms, hydrogen, the group R₃ NR₄, or the group R₅ R₆ ; in which R₃ is asecondary alcohol group with 1 to 6 carbon atoms, R₂ is an alkene, anester, an aldehyde group, a carboxylic acid group or a ketone group with3 to 6 carbon atoms, the group R₇ N--COR₈, or the group --CONHR₉ inwhich R₇ is an alkyl group with 1 to 6 carbon atoms, R₈, R₉ are alkylgroup with 1 to 12 carbon atoms R₄ is an alkyl group with 1 to 8 carbonatoms, R₅ is an alkyl group with 1 to 4 carbon atoms, R₆ is a cyclicoxygen containing group with 2 to 4 carbon atoms, provided that when R₁is hydrogen, R₂ is a ketone group with 3-6 carbon atoms.

Another object of the invention is to provide β-adrenergic blockerscompositions and a method of treatment of patients in need of treatment.

Another object of the invention is to provide processes for thepreparation of the novel compounds and to pharmaceutical compositionscomprising the same.

This invention has shown that even a minor chemical modification of thesubstituents on the aromatic ring of guaiacol-based compounds may resultin a marked reduction of pain-producing potency and lead to a completeloss of antinociceptive activities, better) β-blockers activity, andless toxicity than that of natural pungent substances.

The reaction schemes are illustrated hereinbelow. The syntheticreactions are preferably carried out in the alkaline solution ofstarting materials like vanillin, and eugenol (formula V) illustratedonly with respect to vanillin, and further reacted with compounds(formula II IV) to produce compound of formula I. According to thereaction scheme hereinbelow compound 2 (dehydrozingerone) wassynthesized from vanillin of formula V, then the compound 2 washydrogenated and converted to compound 1(zingerone). Treating compound 2with the compound of formula II gave compound 3; amination of compound 3with the compounds of formula IV in alcoholic solution produced thecompound 4 or 6. The compound 5 was synthesized from compound 1 orhydrogenated from compound 4. R₅ is alkyl group with 1 to 4 carbonatoms, R₆ is a cyclic oxygen containing group with 2 to 4 carbon atomsand preferably the total number of carbon atoms of R₅ and R₆ is lowerthan six. ##STR3##

The R₃ is a secondary alcohol group with 1 to 6 carbon atoms. R₄ is analkyl group with 1 to 8 carbon atoms and preferably the total number ofcarbon atoms of R₃ and R₄ is lower than six. As a suitable base, one mayinclude an inorganic base such as an alkali metal hydride, for instancesodium hydride, or an alkali metal hydroxide, eg. sodium hydroxide,potassium hydroxide, or an alkali metal carbonate, eg. sodium carbonate,or an alkaline earth metal hydroxide, for instance magnesium hydroxide,or the like.

In formula I, the O R₁ group may be a methoxy group in the metaposition, and R₂ on the para position with respect to the O R₁ group.The structure of all compounds were supported by data derived frommelting points, infrared(IR) and nuclear magnetic resonance (NMR)spectra, mass spectra.

The guaiacoxy- propanolamine derivatives according to the presentinvention and also their salts display useful pharmacologicalproperties. When R₁ is hydrogen, the salts or the compounds are thesodium salts, potassium salts, calcium salts, or magnesium salts. Theformula I compounds and their pharmaceutically acceptable salts areselective β-adrenergic blockers, antagonists of platelet aggregation,and β-receptor binding.

The compounds according to this invention are useful as a medicine forthe prevention of thrombosis. The following tests are given for thepurpose of illustrating the pharmacological activity.

TEST 1

Test Method

The wiping test was performed as described by Szolcsanyiand,Jancso-Gabor. Briefly, the solution or suspension of the test compoundand its analogs was made up in 10% ethanol, 5% Tween 80 and then dilutedwith saline to the required concentrations. Each solution or suspensionof 10⁻⁴ M, 10⁻³ M, 10⁻² M was dropped into the right eye (vehicle beingadministered to the left eye as negative control) of male Wistar ratsweighing 180-250 g and the total number of protective movements(scratching, wiping of the eye with the foreleg) was counted for 30minutes. Each test was carried out with a total of 6 rats, and adose-response curve was obtained from the mean value of each group. MPPs(the concentrations having a moderate pain-producing potency) werecalculated from the dose-response curve and those concentrationsinducing equal reactions of 32 scratchings were recorded.

Test Compounds

4-(4'-hydroxy-3'-methoxyphenyl)-3-butan-2-one (zingerone,1)

4-(4'-hydroxy-3'-methoxyphenyl)-3-buten-2-one (Dehydrozingerone, DZ,2)

4- 4'-(2,3-Epoxypropoxy)-3'-methoxyphenyl!e-3-buten-2-one (DZE,3)

4-4'-(2-hydroxy-3-isopropylaminopropoxy)-3'-methoxyphenyl!-3-buten-2-one(DZN, 4)

4-4'-(2-hydroxy-3-tertbutylaminopropoxy)-3'-methoxyphenyl!-3-buten-2-one(DZBN,6)

Test Result

Based on the obtained MPP values, RPP (relative pain producing potency)values were determined with respect to the pain-producing potency of 1,which was taken as 1000. As shown in FIG. 1, the pain producing potencyof compounds 4 and 6 of DZN and DZBN is lower than that of DZ andzingerone.

TEST 2

Test Method

Following the method described by Koster antinociceptive tests werecarried out in male mice after intraperitoneal administration of testsolution. Briefly, four groups of eight male mice (ddk strain) weighing18-22 g were brought to the laboratory on the day prior to study, andhoused overnight with free access to food and water. Solutions ofcompound 1 and its analogs as well as indomethacin were made up in 10%ethanol, 10% Tween 80 and 80% saline, and then diluted with saline tothe required concentrations. The test solution was administered byintraperitoneal injection of a single dose 0.2 ml (vehicle administeredas control). Twenty minutes after injection, 0.2 ml of 0.7% acetic acidwas injected intraperitoneally to induce writhing. Following theinjection, the mice were placed in separate clear glass cages and thenumber of writhes was counted for 18 consecutive 5 minute periodsbeginning 5 minutes after the acetic acid injection, a writhe beingdefined as a sequence of arching of the back followed by pelvic rotationand hind limb extension.

The compounds tested were:

4-(4'-hydroxy-3'-methoxyphenyl)-3-butan-2-one (zingerone,1)

4-(4'-hydroxy-3'-methoxyphenyl)-3-buten-2-one(Dehydrozingerone DZ,2)

4- 4'-(2,3-Epoxypropoxy)-3'-methoxyphenyl)!-3-buten-2-one (DZE,3)

4-4'-(2-hydroxy-3-isopropylaminopropoxy)-3'-methoxyphenyl!-3-buten-2-one(DZN, 4)

The ED50 values reported in Table 1 show significant variations inantinociceptive effect, zingerone is 3 times more potent than DZ. ED50is the effective dose for 50% of the animals.

                                      TABLE 1                                     __________________________________________________________________________    Comparison of antinociceptive effects of                                      zingerorie analogues on acetic acid-induced                                   writhing syndrome.                                                                  Dose   Writhes No.                                                                          Protection                                                                         ED.sub.50 (95% C.I.)                                                                  Potency                                      Compound                                                                            (mg/kg)                                                                           N  (Ave. ± S.E.)                                                                     (%)  (mg/kg) ratio                                        __________________________________________________________________________    Saline    24 80.14 ± 5.13                                                                      0                                                         Zingerorie                                                                          0.25                                                                              8  47.13 ± 4.49                                                                      10.82                                                                              0.25 (1.06-0.06)                                                                      1.50                                               1.25                                                                              8  20.75 ± 3.40                                                                      71.10                                                           2.50                                                                              8   4.00 ± 2.20                                                                      95.01                                                     DZ    0.25                                                                              8  58.13 ± 5.71                                                                      27.46                                                                              0.38 (0.82-0.17)                                                                      1.00                                               1.25                                                                              8  29.60 ± 3.75                                                                      63.06                                                           2.50                                                                              8   2.33 ± 0.83                                                                      97.09                                                     DZE   0.25                                                                              8  46.67 ± 2.09                                                                      41.76                                                                              0.23 (0.88-0.06)                                                                      1.70                                               1.25                                                                              8  27.50 ± 3.32                                                                      65.69                                                           2.50                                                                              8  13.86 ± 1.82                                                                      132.71                                                    DZN   0.25                                                                              8  29.80 ± 5.73                                                                      62.82                                                                              0.11 (0.60-0.02)                                                                      3.50                                               1.25                                                                              8  11.17 ± 2.36                                                                      86.06                                                           2.50                                                                              8   3.20 ± 0.23                                                                      96.01                                                     __________________________________________________________________________     a: Writhes were counted for 30 min after acetic acid injection (i.p.)         b: Protection (%) = 100 - (experimental/control × 100)                  c: ED.sub.50 's and 95% confidence intervals were calculated by the           Litchfield and Wilcoxon method                                           

FIG. 2 shows the total numbers of writhes of the compounds tested.

TEST 3

Test Method

Anesthesed rats were administered intravenously DZN (compound 4) in theamounts of 0.1, 0.5, 1.0 mg/kg, Propranolol and isoproterenolol wereadministered as control. The effect of DZN on heart rate and bloodpressure were monitored.

Test Compound

4- 4'-(2-hydroxy-3-isopropylaminopropoxy)-3'-methoxyphenyl!-3buten-2-one(DZN,4)

Test Results

(1) As shown in FIGS. 3-6 DZN induced dose-dependent bradycardia andthis effect lasted over 1 hr. DZN and propranolol slightly reduced theblood pressure for 5-10 minutes after injection. Statisticalsignificance was not found.

(2) As FIGS. 6(A) and 6(B) show the 0.5 mg/kg isoproterenolol increasedthe heart rate and decreased blood pressure of rats. Propranololantagonized the effects of isoproterenolol. These results are inagreement with the findings of Baird, J. R. C. et al (J. Pharm.Pharmac., vol. 24, 880-85, 1972). DZN compound 4 not only reducedresting heart rate but also lowered the blood pressure induced byisoproterenolol.

(3) The ID₅₀ value of propranolol induced heart rate change was 0.14mg/kg, and that of DZN was 0.22 mg/kg (Table 2) calculated by the methodof Litchfield, J. L. et al (J. Pharmacol. Exp. Ther., vol. 96, 99-113).The ID₅₀ value is the response of a β drug which produces a response in50% of a drug.

                  TABLE 2                                                         ______________________________________                                        ID.sub.50 Heart Rate response of various β-adrenergic                    blocking agents                                                               ______________________________________                                        β- Adrenergic  ID.sub.50 : heart rate                                    blocking agent      response (95% C.I.)                                                           (mg/kg)                                                   Propranolol         0.14 (0.96-0.02)                                          DZH (compound 4)    0.22 (1.29-0.04)                                          ______________________________________                                    

TEST 4

Test Method

(1) The test was conducted according to the method described by Malta,E. (BR.J.Pharmac., vol. 85, 179-87, 1985) 0.50 μM of phenoxybenzaminewas first applied to the 10 ml organ bath of isolated guinea pig rightatrium to block the response of β1 adrenergic receptor. A series ofdoses of isoproterenolol from 10⁻¹⁰ -3×10⁻⁸ M were then introduced intothe bath. A bath as described in Gen. Pharmacology 25 p 652 is used toput in the solution of the drug and the organ is hung within the bathand the contraction or relaxation response is shown on a transducer

(2) The isolated guinea pig right atrium was pretreated with DZN, andthen given isoproterenolol described as above.

Test Compound

4-4'-(2-hydroxy-3-isopropylaminopropoxy)-3'-methoxyphenyl!-3-buten-2-one(DZN, compound 4)

Test Results

(1) The effects of isoproterenolol on contraction force and beating rateof right atrium are dose-dependent. The maximum effect was obtained at3×10⁻⁸ M isoproterenolol (FIG. 7).

(2) To obtain the maximum effect of beating rate, a concentration ofisoproterenolol is required higher than that of control group (FIGS. 7and 8). After the treatment with DZN, the sigmoid curveisoproterenolol-dependent concentration effect was partially shifted tothe right as shown in FIG. 9. A very close phenomenon was seen when DZNwas replaced with propranolol. The estimated pA₂ values of DZN andpropranolol were 8.16 and 8.36, respectively. Regression analysisrevealed a strong correlation between the doses of antagonists andisoproterenolol (FIG. 10).

As described in "Manual of pharmacological calculation with computerprograms, New York: Springer Verlag: 1987. by Tallarida, R. J.; Murray,R. B.", the pA₂ is a measure of the affinity of a competitive antagonistfor its receptor. The determination of the pA₂ is made from experimentsin which a fixed concentration of the antagonist is used along withgraded concentrations of an agonist acting on the same receptor. Thepresence of the antagonist shifts the agonist dose-response curve to theright.

TEST 5

Test Method

(1) The method developed by Piercy, V. et al (J. Pharmac. Methods., vol.20, 125-33, 1988) was employed for this experiment. Female rats wereintraperitonealy injected with stilbestrol (1 mg/kg) to elevate thesensitivity of β₂ adrenergic receptor in uterus horns. The rats weresubsequently administered reserpine to deplete the catecholamine inuterus. The isolated uterus horns were treated with phenoxybenzamine toblock the neuronal uptake and the interaction between neuron cells andthe adrenergic receptor.

Test Compound

4-4'-(2-hydroxy-3-isopropylaminopropoxy)-3'-methoxyphenyl!-3-buten-2-one(DZN,4)

Test results (1) When a krebs' solution was used as the rinsingsolution, a fast contraction in the uterus smooth muscle was observedafter depolarization, then the muscle relaxed and reached a steadystate. Isoproterenolol ranging from 10⁻⁸ -10⁻⁶ M was added. Adose-related decrease in relaxation force was observed in the smoothmuscle of isolated uterus horns (FIG. 11).

(2) Pretreatment of the isolated uterus horns with 10⁻⁸ -10⁻⁶ M DZNcaused the concentration of isoproterenolol needed to reach the maximumrelaxation effect to be increased as shown in FIGS. 11 and 12.Pretreatment with DZN led the concentration effect curve ofisoproterenolol to partially shift to the right (FIG. 13); the pA₂ valueof DZN was 7.53. The estimated slope of the regression analysis was0.99±0.11 (FIG. 14).

(3) Compared to isoproterenolol and DZN, propranolol produced aregression slope of 0.99±0.12 and a pA₂ values of 8.33 in itsconcentration-effect curve. As summarized in Table 3, thecardioselectivity of DZN was 4.26 according to the pA₂ values obtainedfrom the log concentration-effect curve.

                  TABLE 3                                                         ______________________________________                                        β-Adrenoceptor blocking potency and cardioselectivity of                 propranolol and DZN on guinea-pig and rat in vitro                            preparations. pA2 values and slopes of regression calculated                  from Schild plots are shown. Cardioselectivity ratio is                       obtained from the antilogarithm of the difference between                     the mean pA2 values obtained from different tissues.                                    β1       β2   Cardiose-                                   β-Adrenoceptor                                                                     guinea-pig right atrium                                                                     rat uterus                                                                              lectivity                                   blocking agent                                                                          (slope)       (slope)   ratio                                       ______________________________________                                        Propranolol                                                                             8.36 ± 0.02                                                                              8.33 ± 0.19                                                                          1.07                                                  (0.97 ± 0.10)                                                                            (0.99 ± 0.12)                                      DZN       8.16 ± 0.03                                                                              7.53 ± 0.10                                                                          4.26                                                  (0.96 ± 0.05)                                                                            (0.99 ± 0.11)                                      ______________________________________                                    

TEST 6

Test Method

Method of receptor binding assay. After punching the heads of guineapigs, the blood was drained and the heart ventricle immediately removed.The ventricles were placed in 10 vols. of ice-cold buffer (250 mMsucrose, 1 mM Magnesium Chloride, 50 mM Tris-HCl, pH 7.5) and allsubsequent procedures were carried out at 4° C. The ventricles werehomogenized using a homogenizer 3-4 times. The period of eachhomogenization took 15 seconds. The initial homogenate was filtered, andthe filtrate was centrifuged at 700 g for 12 minutes. The supernatantwas further centrifuged at 10,000 g and the final pellet was resuspendedin a small volume of 75 mM Tris buffer containing 25 mM MagnesiumChloride. The membrane protein content was determined by a protein assaydye. The receptor binding assay was initiated by incubating 100 μl of, amembrane protein solution with 50 μl of ³ H!-dihydroalprenolol(³ H-DHA)and the competing drugs. Additional buffer was added to increase thereaction volume up to 250 μl. The binding reaction was activated at 25°C. water by constantly shaking for 60 minutes. The binding reaction wasstopped by diluting it with 1 ml of ice-cold assay buffer. The solutionwas then filtered on a Whatman GF/C glass fiber filter paper undervacuum suction. The filters were washed 3 times with ice-cold assaybuffer and dried at 60±C. in an oven for 2 hrs. Then 4 ml ofscintillation fluid was added and the radioactivity was counted onβ-counter.

Test Compounds

4-4'-(2-hydroxy-3-isopropylaminopropoxy)-3'-methoxyphenyl!-3-buten-2-one(DZN,4)

4-4'-(2-hydroxy-3-tert-butylaminopropoxy)-3'-methoxyphenyl!-3-buten-2-one(DZBN,6)

4- 4'-(2-hydroxy-3-isopropylaminopropoxy)-3'-methoxyphonyl!-2-butanone(ZPN,9)

Test Results

As shown in FIG. 15 and Table 4, the IC₅₀ values of DZBN6 and DZN4 areclose to the IC₅₀ values of the well known β-adrenergic agonistAtenolol. The term IC₅₀ is Inhibitory Concentration at 50%, which meansthe effective concentration of antagonist (or blocker) such as DZBN toinhibit (or decrease) the maximal efficacy of agonist such asisoproterenolol to the half of this maximal efficacy.

                  TABLE 4                                                         ______________________________________                                        EC.sub.50 (M) value osf various β-adrenergic                             antagonists                                                                   β-antagonists    EC.sub.50 (M)                                           ______________________________________                                        (-)Propranolol        1.1 × 10.sup.-8                                   (±)DZBN            3.6 × 10.sup.-6                                   (±)ZPN             1,1 × 10.sup.-5                                   (±)DZN             1,3 × 10.sup.-6                                   (±)Atenolol        3.5 × 10.sup.-5                                   ______________________________________                                    

TEST 7

Test

Effect of addition of isoproterenolol in different concentration to theisolated rat right atrium pretreated with reserpine.

Test Compounds

4-(4'-hydroxy-3'-methoxyphenyl)-3-buten-2-one(Dehydrozingerone DZ,2)

4-4'-(2-hydroxy-3-isopropylaminopropoxy)-3'-methoxyphenyl!-3-buten-2-one(DZN,4)

Test Results

(1) FIG. 16 shows that isoproterenolol increases the heart rate andcontraction force.

(2) The concentration effect curve indicated that the maximum effect wasachieved at 3×10⁻⁶ M isoproterenolol (FIG. 17).

(3) The effect of DZN was different from that of isoproterenolol; DZNreduced the heart rate at concentration about 10⁻⁶ M. On the other hand,DZ compound 2 did not affect the heart rate within 10⁻⁹ -10⁻⁵ M.

TEST 8

Test

The platelet aggregation test was conducted by the method reported byYeh, H. I. et al (Thromb.Res., vol. 45,39-49, 1987), or Srivastava, K.C. et al (Leuk.Med., vol. 29, 79-84, 1987) as reference.

Test Compounds

4-(4'-hydroxy-3'-methoxyphenyl)-3-butan-2-one (zingerone,1)

4-(4'-hydroxy-3'-methoxyphenyl)-3-buten-2-one(Dehydrozingerone DZ,2)

4- 4'-(2,3-Epoxypropoxy)-3'-methoxyphenyl!-3-buten-2-one (DZE,3)

4-(4'-(2-hydroxy-3-isopropylaminopropoxy)-3'-methoxyphenyl!-3-buten-2-one(DZN, 4)

Test Results

A monophasic aggregation curve was observed when 10 μg/ml of collagenwas added to platelet rich plasma (PRP). Pretreatment of the plateletrich plasma with propranolol, Zingerone, DZ, DZE, and DZN caused adose-dependent inhibition of platelet aggregation induced by collagen.As seen in FIG. 18, the platelet aggregation was completely inhibited by250 μM propranolol, 100 μM Zingerone, 250 μM DZ-2, 100 μM DZE-3, 250 μMDZN-4.

TEST 9

Test Method Statistical Methods

The test was conducted according to the method described by Litchfield,J. L. et al (J. Pharmacol.Exp.Ther., vol. 96, 99-113).

The compounds tested were:

4-(4'-hydroxy-3'-methoxyphenyl)-3-buten-2-one(Dehydrozingerone DZ,2)

(4-4'-(2-hydroxy-3-isopropylaminopropoxy)-3'-methoxyphenyl!-3buten-2-one(DZN,4)

Test Results

The LD₅₀ 's values are shown in Table 5.

                  TABLE 5                                                         ______________________________________                                        Acute toxicity of propranolol, DZH and DZ in                                  mice.                                                                                              LD.sub.50 (95% C.L.).sup.a                               Compound      Route  (mg/kg)                                                  ______________________________________                                        Propranolol   p.o.   446.92 (303.08-659.04)                                                 i.p.   288.79 (200.13-416.72)                                   DZN           p.o.   >1000                                                                  i.p.   >1000                                                    DZ            p.o.   >1000                                                                  i.p.   >1000                                                    ______________________________________                                         a: LD.sub.50 's and 95% confidence limits were calculated by Litchfield       and Wilcoxon method.                                                     

The compounds of formula I and their pharmaceutically acceptable acidaddition salts can be used as medicaments, eg. in the form ofpharmaceutical preparations for enteral, parenteral, topical or oralapplication. The manufacture of the pharmaceutical compositions may becarried out in a manner which is familiar to any person skilled in theart by using the described compounds of formula I and theirpharmaceutically acceptable acid addition salts, optionally incombination with other therapeutically valuable subcutaneous substancessuch as corn starch, starch, lactose, sodium carboxymethylcellulose,ethanol. The β-adrenergic blocker compositions to be used orally containabout 60 mgs. per dose of a compound according to the present invention.

Vaninolol of formula hereinbelow ##STR4## has been shown to lower theintraocular pressure (IOP) and is useful in the treatment of glaucoma inthe form of an eye solution.

This 4-4'-(2-hydroxy-3-tert-butylaminopropoxy)-3'-methoxyphenyl!-3-buten-2-one(DZBN) compound 6 is watersoluble and exhibits lower pungency so that itis preferred for parenteral and eye solution. The preferred individualdosage is 0.25 %, 0.5% eye solution and may be administered up to twicedaily.

The following examples and preparation are given for the purpose ofillustration of this invention.

EXAMPLE 1 (Dehydrozingerone, DZ,2)

Aqueous sodium hydroxide 30% was slowly added to 50 g vanillin at atemperature lower than 25° C. After the dropwise addition of 7 moleacetone, the heterogeneous mixture was stirred for a further 48 hours.The solution was then treated with hydrochloric acid until the pH was6.5 and was allowed to stand overnight until a precipitate separated.The solution was filtered and the filtrate was evaporated. The residueis recrystallized from methanol to give4-(4'-hydroxy-3'-methoxyphenyl)-3-buten-2-2one(Dehydrozingerone,-DZ,2)as yellow crystal.

mp: 125°-126° C.

UV λmax nm (log ε): 241.5(4.12),337(4.43).

¹ H-NMR(CDCl₃): δ7.46(d,1H, CH═CH), 6.92-7.14(m,3H, Ar), 6.59(d,1H,Ar--CH), 6.25(s,1H, OH), 3.93(s,3H, OCH₃), 2.37(s, 3H, CH₃).

IR (KBr): 1650 cm⁻¹ (carbonyl,C=0),1595 cm⁻¹ (conjugated C═C).

FAB-MS m/z: 193 M+H!⁺.

Anal(C₁₁ H₁₂ O₃) C.H.

EXAMPLE 2 4- 4'1-(2,3-Epoxypropoxy)-3'-methoxyphenyl!-3-buten-2-one(DZE,3)

20 g Dehydrozingerone and 4 g NaOH were dissolved under stirring inabsoluted ethanol overnight. Then 5 ml chlorohydrin was added and thenheated. After cooling, the inorganic salt was filtered off, the filtratewas diluted with methanol, and then treated with conc. HCl to pH 7.0.The separated solid was recystallized from ethanol to afford 4-4'-(2,3-epoxypropoxy)-3'-methoxyphenyl!-3 buten-2-one (DZE, 3) 75% ascolorless needles.

mp: 123°-124° C.

UV λmax nm (log ε): 239.5(4.16), 331(4.41).

¹ H-NMR(CDCl₃): δ7.42-7.50 (d,1H, CH═CH), 6.92-14(m,3H, Ar 6.57-6.65(d,1H, Ar--CH), 4.02-4.37(m,2H, CH₂ OAr), 3.92(s,3H, OCH₃), 3.40-3.42(brs,1H, CHO), 2.75-2.95(m,2H, CH₂ of the epoxide), 2.38(s,3H, CH₃).

IR (KBr): 1650 cm⁻¹ (carbonyl, C=0).

FAB-MS m/z: 249 M+H!⁺.

Anal(C₁₄ H₁₆ O₄) C.H.

EXAMPLE 3 4-4'-(2-hydroxy-3-isopropylaminopropoxy)-3'-methoxyphenyl!-3-buten-2-one(DZN,4)

To 10 ml of isopropylamine were added 10 g of DZE (3) and 50 ml ethanol.The mixture was heated under reflux at 55° C. for 1 hr. The mixture wasthen evaporated in a rotary evaporator. The residue was extracted withether, and recrystallized from benzene to give 4-4'-(2-hydroxy-3-isopropylaminopropoxy)-3'-methoxyphenyl!-3-buten-2-one(DZN,4)45%, as pale yellow crystals.

mp: 109°-110° C.;

UV λmax nm (log ε): 330(4.39).

¹ H-NMR(CDCl₃): δ42-7.50(d,1H, CH═CH), 6.89-7.08(M,3H, Ar), 6.56-6.65(d,1H, Ar--CH), 4.07(m,3H, OCH₂ CHO), 3.89(s,9,3H, OCH₃),2.80-2.86(s,3H, CH₂ NHCH), 2.57(br s,2H, exchangeable OH & NH),2.37(s,3H, CH₃), 1.08-1.11(d,6H, CHMe₂) ^(o)

IR (KBr): 3300 cm⁻¹ amine(N-H), 1650 cm⁻¹ carbonyl(C=0).

FAB-Ms m/z: 308 M+H!⁺.

Anal(C₁₇ H₂₅ NO₄) C.H.N.

EXAMPLE 4 4-4'-(2-hydroxy-3-(isopropylaminopropoxy)-3'-methoxyphenyl!-2-butanone(ZPN,5)

1 g DZN (compound 4) was dissolved in ethanol and reduced with hydrogenusing platinum oxide as catalyst 70° C. and 60 p.s.i. After filteringoff the platinum oxide, the filtrate was evaporated and recrystallizedfrom methanol to afford 4-4'-(2-hydroxy-3-(isopropyamino)propoxy)-3'-methoxyphenyl!-2-butanoneZPN,5) 90% as pale yellow crystals,

¹ H-NMR(CDCl₃): δ6.68-6.86(m,3H, Ar), 4.07(m,3H, OCH₂ CH), 3.85(s,3H,OCH₃), 2.74-2.88(m,7H, CH₂ CH₂ &CH₂ NHCH), 2.15(s,3H, CH₃),1.10-1.13(d,6H, CHMe₂).

FAB-MS m/z: 310 M+H!⁺.

Anal (C₁₇ H₂₇ NO₄) C.H.N.

EXAMPLE 5 4-4'-(2-hydroxy-3-tert-butylaminopropoxy)-3'-methoxyphenyl!-3-buten-2-one(DZBN,6)

To 10 ml of tert-butylamine were added 100 g of DZE(3) and 50 ml ofabsoluted methanol. The mixture was heated under nitrogen at 55° C.reflux for 2 hrs. The mixture was evaporated in a rotary evaporator andthen dichloromethane(CH₂ Cl₂) was added and let stand overnight. Theprecipitate which separated was filtered off and recrystallized from CH₂Cl₂ to give 4-4'-(2-hydroxy-3-tert-butylaminopropoxy)-3'-methoxyphenyl!-2-butenone(DZBN, 6) 75% as pale yellow crystals.

mp 96°-97° C.

¹ H-NMR(CDCl₃): δ7.52-7.60(d,1H, C═CHCO), 7.07-7.45(m,3H, Ar),6.7-6.8(d,1H, ArCH), 4.98(br,1H, OH), 3.9-4.05(m, ArOCH₂ CH), 3.8(s,3H,OCH₃), 2.5-2.7(m,3H, CH₂ NCH), 2.3(s,3H, COCH₃), 1.03(s,9H, CH₃ ×3).

IR (kBr): 3300, 1690, 1595, 1510, 1270, 1150, 810 cm⁻¹ .

FAB-MS m/z: 322 M+H!⁺.

Anal(C₁₈ H₂₇ NO₄) C.H.N.

EXAMPLE 6 N-4-0-(2-hydroxy-3(isopropylamine)propoxy)-3-methoxyphenyl!-2-propylene

8 g sodium hydroxide was dissolved in 130 ml ethanol and then were added80 ml epichlorohydrin and 38 g Eugenol. The mixture was heated under 70°C. for 1.5 hrs, after cooling, it was reacted with 50 ml isopropylamine.The precipitate solid product is filtered off and recrystallized fromethylacetate to afford N- 4-0-(2-hydroxy-3(isopropylamine)propoxy)-3-methoxyphenyl!-2-propylene 85% as colorless crystals.

mp 63°-64° C.,

¹ H-NMR, CDCl₃ : δ1.06(d,6H,CH₃ ×2), 1.98(br 1H,OH,exchangable),2.6-2.9(m, 3H,CH₂ --N--CH), 3.35(d,2H,ArCH₂), 3.85(S,3H,OCH₃),3.9-4.1(m,3H,--CH--CH₂ --O), 5.03-5.14(m,2H, --C═CH₂),5.85-6.1(m,1H,HC═C), 6.7-6.9(m,2H,Ar).

IR (kBr): 3400, 3300, 1525, 1475, 1250, 1040 cm₋₁ .

Anal(C₁₆ H₂₅ NO₃) C.H.N

EXAMPLE 7 N-( 4-o-(2,3-epoxypropoxy)-3-methoxy benzyl!-nonamide,NVAE)

Three grams of sodium hydroxide was dissolved in 60 ml ethanol and 30 mlepichlorohydrin and 10 g (34 m mol) nonivamide were added. The mixturewas heated at a temperature lower than 80° C. for 3 hrs. The filtratewas evaporated and recrystallized from absoluted ethanol to give N-4-o-(2,3-epoxypropoxy)-3-methoxy benzyl!-nonamide, NVAE) 85% ascolorless crystals.

mp 124°-125° C.

UV λmax nm (log ε): 228.5(3.98), 278(3.48).

¹ H-HMR (CDCl₃): δ0.87(t,3H,CH₃), 1.26(m,10H,CH₂ ×5), 1.65(s,2H,CH₂ ×1),2.20(t,2H,CH₂ ×1), 2.74-2.90(m,2H,epoxy CH₂), 3.36(br s,1H,epoxy CH₂),3.86(s,3H, OCH₃), 4.03-4.12(dd,2H,Ar--CH₂), 4.36(d,2H,Ar--CH₂),5.71(s,1H,NH), 6.81-6.91(m,3H,Ar).

IR (KBr) 1640, 1600, 1220 (cm₋₁).

FAB-MS m/z: 349 M!₊.

Anal(C₂₀ H₃₁ NO₁) C.H.N.

The following compounds were prepared in the same manner as describedhereinabove.

EXAMPLE 8 N-4-o-(2-hydroxy-3-(isopropylamino)propoxy)-3-methoxybenzyl!-nonamide,NVAEN)

mp: 120°-121° C.

UV λmax nm (log ε): 228.5(3.95), 278(3.47).

¹ H-NMR(CDCl₃): δ0.87(t,3H,CH₃), 1.11(d,6H,CH₃ ×2), 1.26-2.24(m,14H, CH₂×7), 2.54(br s,1H,exchangeable,OH), 2.70-2.90(m,3 h,CH₂ --NH--CH)3.83(s,3H,OCH₃), 3.95-4.06(m,3H,Ar--OCH₂ --CH(OH)--),4.35(d,2H,Ar--CH₂), 5.71(s,1H,NH), 6.81-6.91(m,3H,Ar).

IR (KBr): 3400,1640 cm₋₁.

FAB-MS m/zs: 408 M!₊.

Anal(C₂₃ H₄₀ N₂ O₄) C.H.N.

EXAMPLE 9 N-4-o-(2-hydroxy-3-(n-propylamino)propoxy)-3-methoxybenzyl!-nonamide

mp: 132°-133° C.

UV λmax nm (log ε): 228(4.23), 277.5(3.73);

¹ H-NMR(CDCl₃): δ0.99 (s,3H,--CH₃), 1.85-1.95(qt,2H,--CH₂ --CH₃),3.05(br s,1H,exchangeable, OH), 3.03-3.38(m,4H,CH₂ --NH--CH₂),4.02(m,3H,Ar--OCH₂ --CH(OH)--),

FAB-MS m/z: 408 M!₊.

Anal(C₂₃ H₄₀ O₄) C.H.N.

EXAMPLE 10 N-4-o-(2-hydroxy-3-(methylamino)propoxy)-3-methoxybenzyl!-nonamide

mp: 101°-104° C.

UV λmax nm (log ε): 229(3.70), 278(3.38);

¹ H-NMR(CDCl₃): δ1.96(br s,1H,exchangeable,OH), 2.47(s,3H,NH--CH₃),2.79(dd,2H,--CH₂ --NH), 4.01(d,2H,Ar--OCH₂), 4.08(m,1H,--CH(OH)--),5.69(s,1H,NH).

PAB-HS m/z: 380 M!₊.

Anal(C₂₁ H₃₆ N₂ O₄) C.H.N.

EXAMPLE 11 N-4-o-(2-hydroxy-3-(ethylamino)propoxy)-3-methoxybenzyl!-nonamide

mp: 102°-103° C.

UV λmax nm (log ε): 229(3.72), 278.5(3.27);

¹ H-NMR(CDCl₃): δ1.12(t,3H,--CH₃), 2.62(br s,1H,exchangeable,OH),2.63-2.83(m,4H,--CH₂ --NH--CH₂), 3.98(d,2H,Ar--OCH2),4.05(m,1H,--CH(OH)--), 5.88(s,1H,NH).

FAB-MS m/z: 393 M!₊.

Anal(C₂₃ H₃₈ N₂ O₄) C.H.N.

EXAMPLE 12 N-4-0-(2-hydroxy-3-(allylamino)propoxy)-3-methoxybenzyl!-nonamide

mp: 98°-99° C.

UV λmax nm (log ε): 228.5(4.18), 278(3.69);

¹ H-NMR(CDCl₃): δ2.40(br s,1H,exchangeable,OH), 2.82(m,2H,--(OH)CH--CH₂--NH--), 3.28(dt,2H,--NH--CH₂ --CH═), 4.02(m,3H,Ar--OCH₂ --CH(OH)--),5.15(m,2H,--CH═CH₂), 5.77(s,1H,NH), 5.89(m,1H,--CH═CH₂)

FAB-HS m/z: 406 M!₊.

Anal(C₂₃ H₃₈ N₂ O₄) C.H.N.

EXAMPLE 13 N-4-o-(2-hydroxy-3-(cyclopropylamino)propoxy)-3-methoxybenzyl!-nonamide

mp: 95°-99° C.

UV λmax nm (log ε): 227(3.71), 278(3.30);

¹ H-NMR(CDCl₃): δ0.40(m,4H, --CH₂ --CH₂ --), 2.19(m,1H,--NH--CH),2.33(br s,1H,exchangeable,OH 2.90(m,2H,--CH--CH₂ --NH--), 4.12(m,3H,Ar--OCH₂ --CH(OH)--), 5.77(s,1H,NH).

FAB-HS m/z: 406 M!₊.

Anal(C₂₃ H₃₈ N₂ O₄) C.H.N.

EXAMPLE 14 N-4-o-(2-hydroxy-3-(n-butylamino)propoxy)-3-methoxybenzyl!-nonamide

mp: 97°-101° C.

UV λmax nm (log ε): 227(4.21), 278(3.74);

¹ H-NMR(CDCl₃): δ0.95(s, 3H, --CH₃), 1.45(m,4H,CH₂ ×2), 2.42(brs,1H,exchangeable,OH), 2.63(t,2H,--NH--CH₂ --), 2.80(m,2H,--CH₂ --NH--),4.02 (m,3H,Ar--OCH₂ --CH(OH)--), 5.78(s,1H,NH).

FAB-MS m/z: 422 M!₊.

Anal(C₂₄ H₄₂ N₂ O₄) C.H.N.

EXAMPLE 15 N-4-o-(2-hydroxy-3-(iso-butylamino)propoxy)-3-methoxybenzyl!-nonamide

mp: 98°-102° C.

UV λmax nm (log ε): 227(4.20), 278(3.72);

¹ H-NMR(CDCl₃): δ0.94(s,6H,CH₃ ×2), 1.75(m,1H,NH--CH₂ --CH--), 2.12(brs,1H,exchangeable,OH), 2.46(d,2H,--NH--CH₂ --CH--), 2.80(m,2H,--CH₂--NH--), 4.04(m,3H,Ar--OCH₂ --CH(OH)--), 5.78(s,1H,NH).

FAB-MS m/z: 422 M!₊.

Anal(C₂₄ H₄₂ N₂ O₄) C.H.N.

EXAMPLE 16 N-4-o-(2-hydroxy-3-(sec-butylamino)propoxy)-3-methoxybenzyl!-nonamide

mp: 97°-101° C.

UV λmax nm (log ε): 228(4.28), 278(3.82).

¹ H-NMR(CDCl₃): δ60.94(m,3H,--CH₃), 1.05(d,3H,--CH(CH₃)--), 2.16(brs,1H,exchangeable,OH), 2.65(m,1H,--NH--CH--), 2.80(m,2H,--(OH)CH--CH₂--NH--), 4.02(m,3H,Ar--OCH₂ --CH(OH)--), 5.78(s,1H,NH).

FAB-MB m/z: 422 M!₊.

Anal(C₂₄ H₄₂ N₂ O₄) C.H.N.

EXAMPLE 17 N-4-o-(2-hydroxy-3-(tert-butylamino)propoxy)-3-methoxybenzyl!-nonamide

mp: 95°-96° C.

UV λmax nm (log ε): 228(3.51), 277.5(3.01);

¹ H-NMR(CDCl₃): δ1.12(s,9H,--CH₃ ×3), 2.47(br s,1H,exchangeable,OH),2.75(m,2H, --CH₂ --NH--C), 3.99(m,3H,Ar--OCH₂ --CH(OH), 5.77(s,1H,NH).

FAB-MS m/z: 422 M!₊.

Anal(C₂₄ H₄₂ N₂ O₄) C.H.N.

EXAMPLE 18 N-4-o-(2-hydroxy-3-(n-pentylamino)propoxy)-3-methoxybenzyl!-nonamide

mp: 95°-99° C.

UV λmax nm (log ε): 228(3.56), 278(3.10);

¹ H-NMR(CDCl₃): δ0.87(m,3H,--CH₃), 1.26(m,4H,--CH₂ ×2), 1.49(t,2H,CH₂×2), 2.75(br s,1H,exchangeable,OH), 2.60-2.82(m,4H,CH₂ --NH--CH₂),3.99(m,3H,Ar--OCH₂ --CH(OH)--), 5.91(s,1H,NH).

FAB-HS m/z: 436 M!₊.

Anal(C₂₆ H₄₄ N₂ O₄) C.H.N.

EXAMPLE 19 N-4-0-(2-hydroxy-3-(3-aminopentylamino)propoxy)-3-methoxybenzyl-!-nonamide

mp: 97°-101 ° C.

UV λmax nm (log ε): 227(4.16), 278(3.72);

¹ H-NMR(CDCl₃): δ0.88(m,6H,--CH₃ ×2), 1.42(m,4H,--CH₂ ×2), 2.42(br s,1H,exchangeable,OH), 2.37(m,1H,--NH--CH), 2.82(m,2H,--CH₂ --NH--),4.00(m,3H,Ar--OCH₂ --CH(OH)--), 5.81(s,1H,NH).

FAB-MS m/z: 436 M!₊.

Anal(C₂₆ H₄₄ N₂ O₄) C.H.N.

EXAMPLE 20 N-4-o-(2-hydroxy-3-(n-hexylamino)propoxy)-3-methoxybenzyl!-nonamide

mp: 93°-97° C.

UV λmax nm (log ε): 227(4.17), 278(3.74);

¹ H-NMR(CDCl₃): δ0.87(m,3H,--CH₃), 1.26(m,4H,--CH₂ ×2), 1.49(t,2H,CH₂×1), 2.75(br s,1H,exchangeable,OH), 2.60-2.82(m,4H,CH₂ --NH--CH₂),3.99(m,3H,Ar--OCH₂ --CH(OH)--), 5.91(s,1H,NH).

FAB-MS m/z: 450 M!₊.

Anal(C₂₆ H₄₆ N₂ O₄) C.H.N.

EXAMPLE 21 N-4-o-(2-hydroxy-3-(cyclohexylamino)propoxy)-3-methoxybenzyl!-nonamide

mp: 95°-99° C.

UV λmax nm (log ε): 227(4.15), 278(3.74);

₁ H-NMR(CDCl₃): δ1.26(s,4H,--CH₂ ×2), 1.67(m,4H,--CH₂ ×2),1.90(d,2H,--CH₂ ×1), 2.21(br s,1exchangeable,OH), 2.43(m,1H,--NH--CH),2.87(m,4H,--CH₂ --NH--), 3.99(m,3H,Ar--OCH₂ --CH(OH)--), 5.76(s,1H,NH).

FAB-MS m/z: 448 M!₊.

Anal(C₂₆ H₄₄ N₂ O₄) C.H.N.

EXAMPLE 22 N-4-o-(2-hydroxy-3-(n-heptylamino)propoxy)-3-methoxybenzyl!-nonamide

mp: 93°-97° C.

UV λmax nm (log ε): 227(3.86), 278(3.42);

¹ H-NMR(CDCl₃): δ0.88(m,3H,--CH₃), 1.26(s,8H,--CH₂ ×4), 1.48(t,2H,--CH₂×1), 2.05(br s,1H,exchangeable,OH), 2.68(dd,2H,--NH--CH₂ --),2.81(m,2H,--CH₂ --NH--), 4.08(m, 3H,Ar--OCH₂ --CH(OH )--),5.78(s,1H,NH).

FAB-MS m/z: 464 M!₊.

Anal(C₂₇ H₄₈ N₂ O₄)

EXAMPLE 23 N-4-o-(2-hydroxy-3-(benzylamino)propoxy)-3-methoxybenzyl!-nonamide

mp: 96°-102° C.

UV λmax nm (log ε): 227(4.17), 278(3.72).

¹ -NMR(CDCl₃): δ2.58(br s,1H,exchangeable,OH), 2.85(m,2H,--CH₂ --NH--),3.81(d,2H,--NH--CH₂ --Ar), 4.01(m,3H,Ar--OCH₂ --CH(OH)--),5.82(s,1H,NH), 7.33(m,3H,--Ar).

FAB-MS m/z: 456 M!₊.

Anal(C₂₇ H₄₀ N₂ O₄) C.H.M.

EXAMPLE 24 N-(4-O-dimethylaminoethyl-3-methoxybenzyl)-nonamide

mp 78°-80° C.

UV λmax nm (log ε): 201(5.47);

¹ H-NMR(CDCl₃): δ0.87(t,3H,CH₃), 1.20-2.25(m,14H,CH₂ ×7),2.39-2.43(s,6H,(CH₃)₂ N), 2.8-2.9(t,2H,NCH₂), 3.85(s,3H,OCH₃),4.13(t,2H, OCH₂), 4.36-4.40(d,2H,ArCH₂), 5.70(br,1H,NH),6.81-6.83(m,3H,Ar).

IR (KBr): 3300, 3100, 2800-3000, 1600, 1500, 1200, 650 cm₋₁.

FAB-MS m/x: 364 M!₊.

Anal (C₂₁ H₃₄ N₂ O₃) C.H.N.

EXAMPLE 25 N-(4-o-4diethylaminoethyl-3-methoxybenzyl)-nonamide

mp: 51°-53° C.

UV λmax nm (log ε): 201(5.14).

¹ H-NMR (CDCl₃): δ0.87(t,3H,CH₃), 1.05-1.13(t,6H,CH₃ ×2),1.20-2.25(m,14H,CH₂ ×7), 2.60-2.75(q,4H,(CH₂)₂ N) 2.95-3.0(t,2H,NCH₂),3.85(s,3H,OCH₃), 4.11(t,2H,OCH₂), 4.32-4.40(d,2H, ArCH₂),5.70(br,1H,NH), 6.78-6.90(m,3H,Ar).

IR (KBr) 3300, 2800-3000, 1620, 1520, 800, 650 cm₋₁.

FAB-MS m/z: 392 M!₊.

Anal(C₂₃ H₄₀ N₂ O₃) C.H.N.

EXAMPLE 26 N-(4-O-pyridylmethyl-3-methoxybenzyl)-nonamide

mp: 99°-101° C.

UV λmax nm (log ε): 280(4.15), 314(3.18), 327(3.20).

¹ H-NMR(CDCl₃): δ0.86(m,3H,CH), 1.25-2.22(m,14H,CH₂ ×7), 3.5(s,3H,OCH₃),3.9(s,2H,NCH₂ --Ar), 4.5(d,2H,OCH--Ar), 5.3(s,1H,CONH), 6.8(m,3H,Ar),7.2-7.8(m,4H,Ar).

IR (KBr): 3300, 2850-3000, 1620, 1525, 1280, 800, 750 cm₋₁

FAB-MS m/z: 385 M!₋.

Anal(C₂₃ H₃₃ O₃ N₃)

EXAMPLE 27 N-(4-O-piperidylethyl-3-methoxybenzyl)-nonamide

mp: 77°-78° C.

UV λmax nm (log ε): 280(3.50).

¹ H-NMR(CDCl₃): δ0.8-0.9(t,3H,CH₃), 1.2-1.6(m,6H,CH₂ ×3),1.2-2.8(m,14H,CH₂ ×7), 3.4(m,3H,CH₂ NCH), 3.7(s,3H,OCH₃),4.0-4.2(m,2H,OCH₃), 6.7-6.8(m,3H,Ar), 8.2(s,1H,CONH).

IR (KBr): 3300, 2850-3000, 1620, 1510, 1220, 800, 750 cm₋₁.

FAB-MS m/z: 403 M!₊.

Anal(C₂₄ H₃₉ N₂ O₃) C.H.N.

EXAMPLE 28

A 0.5% drop eye solution is prepared, for example, as follows.

dehydrozingerone(DZ) 500 mg

NaCl 0.9% 100 C.C

EXAMPLE 29

A 0.25% drop eye solution is prepared, for example, as follows.

DZBN(6) 250 mg

NaCl 0.9% 100 C.C

TABLES 6 and 7 Summarize the Properties of the Guaiacoxypropanolaminesof the Present Invention

                                      TABLE 6                                     __________________________________________________________________________    Heart Rate and Blood Pressure Changes of Rats Induced by                      Guaiacoxypropanolamines                                                        ##STR5##                                                                               change in BP (mmHg) or HR (beats/min) at the following times                  after dosing.sup.a                                                  R         5 min  10 min 15 min 30 min 60 min                                  __________________________________________________________________________    NHCH.sub.3                                                                           BP -1.11 ± 2.31                                                                      -0.22 ± 2.10                                                                      -0.56 ± 1.65                                                                       1.89 ± 2.14                                                                      0.78 ± 1.37                                 HR -34.56 ± 6.79.sup.c                                                               -17.33 ± 5.31.sup.b                                                               -12.22 ± 4.33                                                                     14.56 ± 7.73                                                                      4.78 ± 4.37                          NHC.sub.2 H.sub.5                                                                    BP  7.44 ± 3.16                                                                       2.56 ± 2.56                                                                       1.11 ± 1.78                                                                      -2.44 ± 3.05                                                                      1.88 ± 1.62                                 HR -38.33 ± 5.94.sup.c                                                               -32.22 ± 5.36.sup.c                                                               -28.00 ± 7.02.sup.b                                                               -21.11 ± 8.75                                                                      2.56 ± 11.66                        NHC.sub.3 H.sub.5                                                                    BP -1.56 ± 2.03                                                                      -2.67 ± 1.96                                                                      -1.89 ± 2.04                                                                      -1.11 ± 2.62                                                                      4.78 ± 4.96                                 HR  -36.78 ± 11.25.sup.b                                                             -28.22 ± 9.00.sup.b                                                               -19.89 ± 9.26                                                                     -5.00 ± 8.72                                                                      -7.56 ± 4.14                         NH-c-C.sub.3 H.sub.5                                                                 BP -0.11 ± 1.09                                                                       3.11 ± 2.78                                                                       3.89 ± 2.92                                                                       3.67 ± 4.10                                                                      2.22 ± 2.32                                 HR -47.67 ± 8.88.sup.c                                                               -38.89 ± 9.47.sup.b                                                               -23.67 ± 10.01                                                                    -11.89 ± 8.73                                                                     -2.67 ± 4.14                         NH-n-C.sub.3 H.sub.7                                                                 BP -1.78 ± 1.71                                                                      -2.56 ± 1.47                                                                      -3.11 ± 1.81                                                                      -2.44 ± 1.66                                                                      -0.56 ± 0.50                                HR -42.56 ± 7.65.sup.c                                                               -35.33 ± 6.05.sup.c                                                               -32.00 ± 5.25.sup.c                                                               -14.11 ± 5.16                                                                     -6.89 ± 4.32                         NH-i-C.sub.3 H.sub.7                                                                 BP -0.44 ± 2.05                                                                      -1.22 ± 2.29                                                                      -2.89 ± 2.03                                                                      -6.67 ± 2.51                                                                      -1.33 ± 0.98                                HR -50.22 ± 7.29.sup.c                                                               -40.78 ± 7.64.sup.c                                                               -35.44 ± 7.32.sup.c                                                               -32.67 ± 9.24.sup.b                                                               -20.00 ± 6.15.sup.b                  NH-n-C.sub.4 H.sub.9                                                                 BP -0.22 ± 1.74                                                                      -1.22 ± 1.59                                                                      -1.22 ± 1.77                                                                       0.11 ± 1.54                                                                      3.33 ± 2.82                                 HR -40.00 ± 3.74.sup.c                                                               -33.78 ± 5.08.sup.c                                                               -26.22 ± 6.56.sup.b                                                               -15.33 ± 5.24                                                                     -3.67 ± 2.55                         NH-i-C.sub.4 H.sub.9                                                                 BP -2.75 ± 2.29                                                                       1.63 ± 2.07                                                                       1.63 ± 1.71                                                                       2.00 ± 1.86                                                                      0.25 ± 1.91                                 HR -39.88 ± 8.60.sup.c                                                               -35.25 ± 7.98.sup.b                                                               -27.13 ± 7.76                                                                      4.13 ± 8.20                                                                      3.13 ± 7.90                          NH-s-C.sub.4 H.sub.9                                                                 BP  4.11 ± 2.76                                                                       4.89 ± 3.37                                                                       3.33 ± 3.74                                                                      -0.88 ± 3.11                                                                      1.22 ± 1.47                                 HR  -38.56 ± 11.30.sup.b                                                             -35.44 ± 12.46                                                                    -32.33 ± 11.96                                                                    -25.11 ± 9.49                                                                     -9.56 ± 7.03                         NH-t-C.sub.4 H.sub.9                                                                 BP  3.13 ± 5.66                                                                       3.38 ± 5.08                                                                       2.38 ± 5.41                                                                       1.25 ± 5.45                                                                      4.63 ± 3.51                                 HR -45.00 ± 4.20.sup.c                                                               -37.75 ± 4.44.sup.c                                                               -29.50 ± 5.31.sup.c                                                               -24.88 ± 8.47.sup.b                                                               -18.50 ± 5.13.sup.b                  NH-n-C.sub.5 H.sub.11                                                                BP -4.67 ± 1.71                                                                      -1.67 ± 1.87                                                                      -0.88 ± 3.00                                                                       3.67 ± 2.66                                                                      2.44 ± 1.96                                 HR -25.11 ± 5.81.sup.c                                                               -23.33 ± 2.41.sup.c                                                               -10.22 ± 2.38.sup.c                                                               -5.78 ± 7.89                                                                      -6.56 ± 4.38                         NHC.sub.5 H.sub.11                                                                   BP -2.78 ± 2.33                                                                      -2.56 ± 1.42                                                                      -3.22 ± 1.78                                                                      -1.33 ± 1.38                                                                      0.67 ± 0.47                                 HR -28.11 ± 9.34.sup.b                                                               -28.89 ± 6.30.sup.c                                                               -22.78 ± 5.04.sup.c                                                               -2.22 ± 7.28                                                                      -3.33 ± 5.69                         NH-n-C.sub.6 H.sub.13                                                                BP -2.22 ± 1.42                                                                      -2.89 ± 1.61                                                                      -4.44 ± 2.93                                                                      -2.11 ± 2.77                                                                      1.89 ± 1.13                                 HR -35.56 ± 8.71.sup.b                                                               -24.11 ± 3.31.sup.c                                                               -14.89 ± 7.10                                                                     -12.67 ± 6.59                                                                     -8.00 ± 5.64                         NH-c-C.sub.6 H.sub.11                                                                BP -4.11 ± 2.89                                                                      -4.22 ± 2.29                                                                      -3.67 ± 2.39                                                                       1.33 ± 2.69                                                                      0.67 ± 2.45                                 HR -32.33 ± 15.44                                                                    -28.44 ± 16.54                                                                    -11.67 ± 9.26                                                                     -1.78 ± 8.96                                                                      2.78 ± 9.64                          propranolol                                                                          BP -2.83 ± 1.81                                                                      -6.33 ± 2.16                                                                      -6.50 ± 3.26                                                                      -4.67 ± 2.66                                                                      2.17 ± 3.29                                 HR -57.28 ± 5.94.sup.c                                                               -63.85 ± 7.18.sup.c                                                               -65.28 ± 8.43.sup.c                                                               -62.57 ± 9.06.sup.c                                                               -52.14 ± 10.93.sup.c                 saline BP  2.52 ± 1.51                                                                       1.42 ± 1.00                                                                       0.72 ± 0.54                                                                       0.52 ± 0.43                                                                      0.41 ± 0.41                                 HR  1.72 ± 1.01                                                                       1.01 ± 0.82                                                                       1.01 ± 0.71                                                                       0.53 ± 0.32                                                                      0.32 ± 0.33                          __________________________________________________________________________     .sup.a Data were expressed as means ± SE (n = 8). Administered iv at a     dose of 1.0 mg ± kg.                                                       .sup.b p < 0.05 as compared to saline.                                        .sup.c p < 0.001 as compared to saline.                                  

                  TABLE 7                                                         ______________________________________                                        pA.sub.2 Values of Guaiacoxypropanolamines on Isolated Guinea Pig Atria        ##STR6##                                                                                  positive      positive                                           R            chronotropic  inotropic                                          ______________________________________                                        propranolol  8.12 ± 0.06 (1.00)                                                                       8.42 ± 0.09 (1.00)                              NHCH.sub.3   6.53 ± 0.12 (0.03)                                                                       7.13 ± 0.02 (0.05)                              NHC.sub.2 H.sub.5                                                                          6.93 ± 0.09 (0.07)                                                                       7.27 ± 0.09 (0.07)                              NHC.sub.3 H.sub.5                                                                          7.03 ± 0.05 (0.08)                                                                       7.60 ± 0.08 (0.15)                              NH-n-C.sub.3 H.sub.7                                                                       6.79 ± 0.01 (0.05)                                                                       7.75 ± 0.07 (0.21)                              NH-i-C.sub.3 H.sub.7                                                                       7.77 ± 0.08 (0.45)                                                                       8.07 ± 0.06 (0.45)                              NH-n-C.sub.4 H.sub.9                                                                       7.23 ± 0.07 (0.13)                                                                       7.27 ± 0.07 (0.07)                              NH-i-C.sub.4 H.sub.9                                                                       6.93 ± 0.06 (0.06)                                                                       7.57 ± 0.11 (0.14)                              NH-s-C.sub.4 H.sub.9                                                                       6.92 ± 0.10 (0.07)                                                                       7.65 ± 0.09 (0.17)                              NH-t-butyl   7.40 ± 0.09 (0.19)                                                                       7.80 ± 0.07 (0.24)                              NH-n-C.sub.5 H.sub.11                                                                      7.19 ± 0.02 (0.12)                                                                       7.55 ± 0.04 (0.14)                              NHC.sub.5 H.sub.11                                                                         7.25 ± 0.10 (0.14)                                                                       7.26 ± 0.08 (0.07)                              NH-n-C.sub.6 H.sub.13                                                                      6.03 ± 0.02 (0.01)                                                                       7.18 ± 0.06 (0.06)                              ______________________________________                                         .sup.a Potency ratio (PR) = Antilog (pA.sub.2 antagonist - pA.sub.2           propranolol) with respect to propranolol.                                

With respect to Examples 7-27 all the cardiovascular pharmacologicalresults are shown in Table 6, Table 7, FIG. 19(A), FIG. 19(B) and FIG.20. All these compounds exhibit a bradycardia effect and beta adrenergicblocking activity. For comparison, the PA2 value of these compounds arelisted in Table 7. Some analogs with a 3-methoxy, 4-hydroxy benzyl orphenyl structure, such as eugenol, isoeugenol, vanillin, ethyl vanillicacid ester, ferulic acid can be used as the starting material tosynthesize beta blockers by reaction with isopropylamine andpropanolamine.

What is claimed is:
 1. A compound which is a member selected from thegroup consisting ofN-4-0-(2,3-epoxypropoxy)-3-methoxybenzyl!-nonamide,NVAE). N-4-(2-hydroxy-3-(isopropylamino)propoxy)-3-methoxybenzyl!-nonamide,NVAEN)N- 4-(2-hydroxy-3-(n-propylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-)-(2-hydroxy-3-(methylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3(ethylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-0-(2-hydroxy-3-(allylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(cyclopropylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-((n-butylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(iso-butylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(sec-butylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(tert-butylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(n-pentylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(3-aminopentylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(n-hexylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(cyclohexylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(n-heptylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(benzylamino)propoxy)-3-methoxybenzyl!nonamideN-(4-0-dimethylaminoethyl-3-methoxybenzyl)-nonamideN-(4-0-diethylaminoethyl-3-methoxybenzyl)-nonamideN-(4-0-pyridylmethyl-3-methoxybenzyl)-nonamide andN-(4-0-piperidylethyl-3-methoxybenzyl)-nonamide.
 2. A method oftreatment of a living subject in need of a B-adrenergic blocker toreduce the blood pressure which consists of administering to saidsubject a composition containing an effective amount of a compound whichis a member selected from the group consisting ofN-4-0-(2,3-epoxypropoxy)-3-methoxybenzyl!-nonamide,NVAE) N-4-(2-hydroxy-3-(isopropylamino)propoxy)-3-methoxybenzyl!-nonamide,NVAEN)N- 4-(2-hydroxy-3-(n-propylamino)propoxy)-3-methoxybenzyl!-nonamide N-4)-(2-hydroxy-3-(methylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3(ethylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-0-(2-hydroxy-3-(allylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(cyclopropylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-((n-butylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(iso-butylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(sec-butylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(tert-butylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(n-pentylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(3-aminopentylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(n-hexylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(cyclohexylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(n-heptylamino)propoxy)-3-methoxybenzyl!-nonamide N-4-(2-hydroxy-3-(benzylamino)propoxy)-3-methoxybenzyl!nonamideN-(4-0-dimethylaminoethyl-3-methoxybenzyl)-nonamideN-(4-0-diethylaminoethyl-3-methoxybenzyl)-nonamideN-(4-0-pyridylmethyl-3-methoxybenzyl)-nonamide andN-(4-0-piperidylethyl-3-methoxybenzyl)-nonamide.
 3. A β adrenegicblocker composition in unit dosage form containing a compound accordingto claim 1 in the amount of 60 mgs per dose and a therapeutically inertcarrier.